DJ1 Linked Neurodegeneration Pathways in New Mouse Models of Parkinson s Disease

帕金森病新小鼠模型中 DJ1 相关神经退行性病变通路

• 批准号: 230746918
• 负责人: Professor Dr. Wolfgang Wurst
• 金额: --
• 依托单位: Luxembourg Centre for Systems Biomedicine (LCSB)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/230746918?language=en
• 关键词: DJ1; Linked; Neurodegeneration; Pathways; New

Parkinson s disease (PD) is a common, age-related chronic neurodegenerative disorder with major motor, but also a number of non-motor disease manifestations that significantly impair the quality of life of afflicted patients and impose a heavy socio-economic burden. Current treatments are symptomatic and can manage most motor symptoms, but there is no cure or disease-modifying therapy. It is therefore essential to gain more insight into PD-relevant neurodegeneration pathways in order to define novel therapeutic opportunities. Major advances have been achieved over the last decade in starting to uncover such pathways by the identification of genetic factors responsible for familial forms of the disease. One such genetic factor is DJ-1. Loss-of-function mutations of DJ-1 are associated with rare recessive forms of familial PD. In vivo, deletion of DJ-1 exacerbates neuronal dysfunction and death in response to MPTP or ischemic brain injury, and its administration or replacement is neuroprotective. To study these pathways, we propose to use genetic mouse models of PD that model specifically neuronal dysfunction and cross them onto DJ-1 deficient mice. The two mouse lines with a PD-relevant phenotype express abnormal, pathogenic forms of alpha-synuclein and LRRK2, respectively, but their phenotype is mild and reminiscent of early or pre-symptomatic PD. Through the removal of DJ-1 in these two models, we expect to unleash neurodegeneration that will induce a phenotype closer to full-blown PD. We will analyze the new models behaviourally, neuropathologically, and, to characterize the neurodegeneration pathways, by a set of omics/systems approaches. To characterize disease progression, we will do these analyses in different age groups: before disease onset, and at peak disease manifestation. We will subject the data to statistical evaluation and network reconstruction to identify potential new key players of disease initiation and progression.

帕金森S病是一种常见的、与年龄相关的慢性神经退行性疾病，以主要运动为主要症状，也是一些非运动性疾病的表现，严重影响患者的生活质量，造成沉重的社会经济负担。目前的治疗方法是有症状的，可以控制大多数运动症状，但没有治愈或改变疾病的疗法。因此，为了确定新的治疗机会，更多地了解帕金森病相关的神经退变途径是至关重要的。在过去十年中，通过确定导致这种疾病家族性形式的遗传因素，在开始发现这种途径方面取得了重大进展。其中一个这样的遗传因素是DJ-1。DJ-1功能缺失突变与罕见的隐性家族性帕金森病相关。在体内，DJ-1的缺失加剧了MPTP或缺血性脑损伤所致的神经元功能障碍和死亡，其应用或替代具有神经保护作用。为了研究这些途径，我们建议使用遗传性帕金森病小鼠模型，该模型专门建立神经元功能障碍的模型，并将它们交叉到DJ-1缺陷小鼠身上。具有帕金森病相关表型的两个小鼠系分别表达异常的致病形式的α-突触核蛋白和LRRK2，但它们的表型较轻，使人想起早期或症状前的帕金森病。通过去除这两个模型中的DJ-1，我们希望释放神经退行性变，从而诱导出更接近于完全发育的帕金森病的表型。我们将从行为学、神经病理学的角度对新模型进行分析，并通过一套组学/系统方法来描述神经退行性变的途径。为了描述疾病进展的特征，我们将在不同的年龄段进行这些分析：发病前和疾病表现高峰期。我们将对这些数据进行统计评估和网络重建，以确定潜在的新的疾病启动和发展的关键因素。

项目成果

The pathogenic LRRK2 R1441C mutation induces specific deficits modeling the prodromal phase of Parkinson's disease in the mouse

• DOI: 10.1016/j.nbd.2017.05.013
• 发表时间: 2017-09-01
• 期刊: NEUROBIOLOGY OF DISEASE
• 影响因子: 6.1
• 作者: Giesert, F.;Glasl, L.;Wurst, W.
• 通讯作者: Wurst, W.

Crybb2 Mutations Consistently Affect Schizophrenia Endophenotypes in Mice

• DOI: 10.1007/s12035-018-1365-5
• 发表时间: 2019-06-01
• 期刊: MOLECULAR NEUROBIOLOGY
• 影响因子: 5.1
• 作者: Heermann, Tamara;Garrett, Lillian;Hoelter, Sabine M.
• 通讯作者: Hoelter, Sabine M.

Analysis of locomotor behavior in the German Mouse Clinic

德国小鼠诊所运动行为分析

• DOI: 10.1016/j.jneumeth.2017.05.005
• 发表时间: 2018
• 期刊: Journal of Neuroscience Methods
• 影响因子: 3
• 作者: Zimprich A;Östereicher MA;Becker L;Dirscherl P;Ernst L;Fuchs H;Gailus-Durner V;Garrett L;Giesert F;Glasl L;Hummel A;Rozman J;de Angelis MH;Vogt-Weisenhorn D;Wurst W;Hölter SM
• 通讯作者: Hölter SM

Serum Response Factor (SRF) Ablation Interferes with Acute Stress-Associated Immediate and Long-Term Coping Mechanisms

• DOI: 10.1007/s12035-016-0300-x
• 发表时间: 2016-12
• 期刊: Molecular Neurobiology
• 影响因子: 5.1
• 作者: Annemarie Zimprich;G. Mroz;Christopher Meyer zu Reckendorf;S. Anastasiadou;Philip Förstner;L. Garrett;S. Hölter;L. Becker;J. Rozman;C. Prehn;B. Rathkolb;K. Moreth;W. Wurst;T. Klopstock;M. Klingenspor;J. Adamski;E. Wolf;R. Bekeredjian;H. Fuchs;V. Gailus-Durner;M. H. Angelis;B. Knöll